Using induced pluripotent stem cell (iPSC) derived microglia to model neuroinflammation in Huntington’s disease

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder characterised by progressive motor and cognitive dysfunction. It is caused by a single mutation in the gene encoding huntingtin; a protein involved in a multitude of cellular processes throughout development. Currently, there are no treatments available to slow the progression of the disease. Much research has focussed primarily on the role of neurons in HD and other CNS disorders, however, emerging roles of glial cells including microglia are shifting the focus towards neuron-glia interactions. Neuroinflammation is now recognised as a fundamental component of HD with microglia being the primary innate immune cells orchestrating this process in the CNS. Disease modelling of HD has predominantly relied upon animal models. However, these lack translatability to humans which has consequently led to the failure of compounds in clinical trials. Induced pluripotent stem cell (iPSC) technology has the potential to provide a platform to model disease using human cells without the reliance upon the scarce supply of primary tissue. A number of published protocols are available to generate CNS cell types including neurons, astrocytes, and microglia from iPSC. In this thesis, inflammatory responses of control and patient microglia in monoculture will be compared along with discussion of the progress towards the development of a platform incorporating neurons, astrocytes, and microglia, to better recapitulate the in vivo CNS microenvironment. Interestingly, patient microglia appear significantly less responsive to LPS compared to controls. The methods used to maintain and differentiate iPSC are xenofree, increasing the relevance to the human condition.